PubMed · 7352592
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J C Kuehnle. 1980. Titrated versus fixed-dose protocols.. https://pubmed.ncbi.nlm.nih.gov/7352592/
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BACKGROUND: Endothelin-1 (ET-1), acting mainly through the ET(A) receptor, is a potent endothelium-derived vasoconstrictor peptide. Circulating concentrations of ET-1 are increased in chronic renal failure (CRF) and may influence vascular tone. METHODS: We investigated dorsal hand vein responsiveness to local infusion of ET-1 and noradrenaline in 12 hypertensive and 12 normotensive CRF patients and in 12 age and sex matched control subjects. We also investigated dorsal hand vein responses to the ET(A) receptor antagonist, BQ-123, and the endothelium-independent vasodilator glyceryl trinitrate (GTN), in six patients with CRF. RESULTS: The dose of noradrenaline causing a 50% of maximal vasoconstriction was similar in the hypertensive (32+/-11 pmol/min) and normotensive (26+/-7 pmol/min) CRF patients and control subjects (21+/-6 pmol/min). Vasoconstriction to ET-1 (5 pmol/min) was similar in CRF patients as a whole (AUC 35+/-5%) and controls (32+/-4%; P=0.70). However, venoconstriction was significantly less in hypertensive (23+/-6%) than in normotensive CRF patients (48+/-8%; P=0.01). Overall, venoconstriction to ET-1 correlated inversely with mean arterial blood pressure in the CRF patients (R=-0.43, P=0.04). In addition, basal vein size was smaller, and plasma endothelin concentrations greater, in the hypertensive CRF group. However, infusion of BQ-123 or GTN did not cause venodilatation in these subjects. CONCLUSIONS: These studies are consistent with the hypothesis that elevated plasma ET-1 contributes to vascular tone, and elevated blood pressure, in hypertensive CRF patients, and is associated with vascular receptor downregulation consequent on the increased exposure to ET-1. The reduced vein size in CRF patients appears to be structural rather than functional in nature. Further long-term studies with endothelin antagonists are required to determine the pathophysiological role of ET-1 in the altered structure and function of blood vessels in patients with CRF.
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BACKGROUND: Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. METHODS AND RESULTS: Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor. CONCLUSIONS: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.